Genetic mechanisms of arterial stiffness in polygenic salt-sensitive hypertension

描述（由申请人提供）：我们的长期目标是阐明原发性或多基因高血压的病因学，重点是阐明高血压易感性和基因-环境相互作用的遗传变异，这些变异会加剧高血压易感性和终末器官疾病。在临床研究中，以脉搏波速度或PWV测量动脉硬化的重要性日益显现，表明PWV增加与心血管结果（中风、冠心病和慢性肾病）相关，这可能是一个可靠的预测参数，但同时也强调了动物模型研究的必要性，以解决机制问题。因此，本研究计划侧重于rfa声明的目标：#1)“在动物模型中探索动脉硬化与高血压发展之间的时间关系”，#2)进行“在（原发性/多基因）高血压背景下导致导管动脉硬化的机制的细胞和分子研究”。为实现这一目标，我们确定了以下优先目标：研究雄性和雌性中风易感达尔S大鼠大动脉硬化（通过高分辨率超声测量主动脉PWV和应变，颈动脉PWV和应变）和盐敏感性高血压（通过无应激24/7收缩压、舒张压、MAP和PP遥测血压分析测量）与中风的时间关系。目标2。明确所有三个血管层主动脉和颈动脉结构的时间和空间变化，以及推定的基因表达变化，这些变化是na诱导的高血压及其终器官并发症病程中动脉僵硬加剧和进展的基础。目标3。通过对F2杂交雄性和雌性大鼠的全基因组扫描，阐明在多基因盐敏感性高血压背景下动脉僵硬的遗传机制的作用，鉴定单独或相互作用导致动脉僵硬的共同和性别特异性数量性状位点（qtl）。总之，这三个目的将阐明在na诱导的卒中易发高血压大鼠模型中，主动脉和颈动脉僵硬与多基因（原发性）高血压和卒中的关系，并深入了解因果细胞、分子和遗传机制。

DESCRIPTION (provided by applicant): Our long term goal is to elucidate the etiology of essential or polygenic hypertension with a focus on the elucidation of genetic variants that underlie hypertension susceptibility and gene-environment interactions which exacerbate hypertension susceptibility and end-organ disease. The emerging importance of arterial stiffening measured as pulse wave velocity or PWV in clinical studies demonstrating the association of increased PWV and cardiovascular outcomes (stroke, coronary heart disease, and chronic kidney disease) has pinpointed a likely robust predictive parameter, but at the same time highlighted the need for animal model studies to address mechanisms. Accordingly, this research proposal focuses on RFA-stated goals: #1) "to explore the temporal relationship between arterial stiffening and the development of hypertension in an animal model", and #2) to conduct "cellular and molecular investigation of mechanisms that lead to conduit artery stiffening in the context of (essential/polygenic) hypertension". To accomplish this we have prioritized the following specific aims: Aim 1. Examine the temporal relation between large artery stiffening (measured as aortic PWV and strain, carotid PWV and strain via high-resolution ultrasonography), and the development of salt-sensitive hypertension (measured via non-stress 24/7 telemetric BP analysis of SBP, DBP, MAP and PP) and stroke in both male and female stroke-prone Dahl S rats. Aim 2. Define the temporal and spatial changes in aortic and carotid artery structure in all three vessel layers, along with putative gene expression changes that underlie Na-induced exacerbation and progression of arterial stiffness along the disease course of hypertension and its end-organ complications. Aim 3. Elucidate the role of genetic mechanisms in the causation of arterial stiffness in the context of polygenic salt-sensitive hypertension via genome-wide scan of F2[Dahl S x Dahl R]-intercross male and female rats identifying common and sex-specific quantitative trait loci (QTLs) that contribute to arterial stiffness individually or interactively. Altogether, these three aims will elucidate the relationship of aortic and carotid arterial stiffness to polygenic (essential) hypertension and stroke in a Na-induced stroke-prone hypertension rat model, as well as give insight into causal cellular, molecular, and genetic mechanisms.